WO2007148755A1 - Novel compound having affinity for amyloid - Google Patents

Abstract

Disclosed is a compound having affinity for amyloid and satisfactorily rapid clearance from a normal tissue and reduced in toxicity including mutagenicity. Specifically disclosed are: a compound represented by the formula (1) and a salt thereof; and a low-toxic diagnostic agent for Alzheimer's disease comprising the compound or the salt thereof. (1) wherein R1 represents a group selected from a hydrogen, a hydroxyl group, a carboxyl group, a sulfate group, an amino group, a nitro group, a cyano group, an alkyl substituent group having 1 to 4 carbon atoms and an alkoxy substituent group having 1 to 4 carbon atoms; R2 represents a radioactive halogen substituent group; and m represents an integer ranging from 0 to 2.

Description

 Specification

 Novel amyloid affinity compound

 Technical field

 [0001] The present invention relates to a compound used for diagnosis of head degenerative diseases. More specifically, the present invention relates to a compound useful for detection of amyloid at a lesion site in the diagnosis of diseases in which amyloid accumulates such as Alzheimer's disease.

 Background

 [0002] Diseases that develop when fibrous proteins called amyloid are deposited in various organs or tissues in the body are collectively called amyloidosis. A common feature of amyloidosis is that fibrillar protein called amyloid rich in β-sheet structure is deposited in various organs or regions throughout the body, causing functional abnormalities in the organs and tissues.

 [0003] Alzheimer's disease (hereinafter referred to as AD and RE), which is a typical disease of amyloidosis, is known as a disease causing dementia. Since this disease is a disease in which amyloid gradually deposits in the brain and causes death, it can be said that this disease has a higher social interest than other amyloidosis. In recent years, with the aging of society in advanced countries, the number of AD patients has increased rapidly, which has become a social problem.

 [0004] According to histopathological aspects, AD is characterized by three intracerebral pathological findings: appearance of senile plaques, neurofibrillary tangles and extensive neuronal loss. Senile plaques are structures with amyloid as the main component, and their appearance is considered to be the first stage of AD development, that is, a pathological finding in the brain that appears more than 10 years before the appearance of clinical symptoms.

[0005] Diagnosis of AD is performed by performing various cognitive function evaluations (for example, Hasegawa scale, ADAS_JCog, MMSE, etc.) after supplementarily combining image diagnosis such as CT and MRI. Yes. However, such a method based on the evaluation of cognitive function has a drawback that the diagnostic sensitivity is low in the early stage of the onset, and the diagnosis result is easily influenced by the cognitive function inherent in each individual. In addition, because a biopsy of the diseased part is indispensable for a definitive diagnosis, it is virtually impossible to make a definitive diagnosis of AD during the life of the patient (non-specialty). Permissible literature 1).

 [0006] On the other hand, it has been reported that the amyloid composing senile plaques is an aggregate of amyloid protein (hereinafter referred to as A), and further, the aggregate of A has a β sheet structure, thereby causing neurocytotoxicity. Many studies have reported this. Based on these findings, the so-called “amyloid cascade hypothesis” has been proposed, in which the deposition of Α / 3 in the brain triggers the formation of neurofibrillary tangles and neuronal loss as downstream phenomena ( Non-patent literature 2).

 [0007] Based on these facts, attempts have recently been made to detect AD in vivo using a compound having a high affinity for amyloid as a marker.

Many of these cerebral amyloid imaging probes have hydrophobic low molecular weight compounds with high affinity for amyloid and high brain migration, and various radionuclides such as ¹¹ C, ¹⁸ F and ¹²³ 1, etc. The compound labeled with Specific examples include 6-yodo-2- [4 '-(N, N dimethylamino) phenyl] benzothiazole (hereafter referred to as TZDM) and 6-hydroxy-1 [4,1 (N methinoreamino) phenyl] benzothiazole ( Hereinafter, various thioflavine derivatives (referred to as 6-OH-BTA 1) (Patent Document 1, Non-patent Document 3), (E) -4-methylamino-4, monohydroxystilbene (hereinafter referred to as SB-13) and (E) -4 stilbene compounds such as dimethylamino-4, -odostilbene (hereinafter referred to as m-I-SB) (Patent Document 2, Non-Patent Document 4, Non-Patent Document 5), 6 2— [4 '-(N, N-dimethylamino) phenyl] benzoxazole (hereinafter referred to as IBOX), 6- [2- (Fluoro) ethoxy] -2- [2- (2-Dimethylaminothiazole 5 Le) ethenyl] Benzoxazole and other Zoxazole derivatives (Non-patent literature 6, Non-patent literature 7), 2_ (1 _ {6 _ [(2 _ fluorethyl) (methyl) amino] _ 2_ naphthyl} ethylidene) malononitrile (hereinafter referred to as FDDNP and Les, ) And other DDNP derivatives (patent document 4, non-patent document 8) and 6_yodo_2 [4 '-(N, N-dimethylamino) phenyl] imidazo

There have been reports of compounds labeled with ¹¹ C and radioactive halogens such as [1,2, _a] pyridine (hereinafter referred to as IMPY) and imidazopyridine derivatives (Patent Document 3, Non-Patent Document 9). In addition, some of these diagnostic imaging probes have undergone human imaging studies and may show radioactive accumulation in the brain that is clearly different from normal cases in AD patients. It has been reported (Non-patent document 10, Non-patent document 11).

Patent Document 1: Japanese Translation of Special Publication 2004—506723

Patent Document 2: JP 2005-504055 gazette

Patent Document 3: Special Table 2005-512945

Patent Document 4: Japanese Translation of Special Publication 2002-523383

Non-Patent Document 1: J. A. Hardy & G. A. Higgins, Alzheimer's Disease: The Amyloid Cascade Hypohesis., Science, 1992, 256, p.184-185

Non-Patent Document 2: G. McKhann et al "" Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease., Neurology, 1984, 34, p.9 39-944

Non-Patent Document 3: Z.-P. Zhuang et al "" Radioiodinated Styrylbenzenes and Thioflavins a s Probes for Amyloid Aggregates. ", J. Med. Chem., 2001, 44, p.1905-1914

 Special Article 4: Masahiro Ono et al, "11 stilbene derivatives as A j3 -aggre gate-specific PET imaging agents for Alzheimer's disease.", Nuclear Medicine and Biology, 2003, 30, p.565- 571

Non-Special Reference 5: H. F. Kung et al, "Novel Stilbenes as Probes for amyloid plaques., J. American Chemical Society, 2001, 123, p.12740-12741

Non-Patent Document 6: Zhi_Ping Zhuang et al., "IBOX (2- (4'-dimethylaminophenyl) -6- iodob ensoxazole): a ligand for imaging amyloid plaques in the brain., Nuclear Medicine a nd Biology, 2001, 28, p.887- 894

Non-Patent Document 7: Furumoto Y et al "" [11C] BF- 227: A New 11C- Labeled 2-Ethenylbe nzoxazole Derivative for Amyloid- β Plaques Imaging., European Journal of Nuclear Medicine and Molecular Imaging, 2005, 32, Sup. L, P759

 ^ Patent Document 8: Eric D. Agdeppa et al, "2-Dialkylamino-6-Acylmalononitrile Substitu ted Naphthalenes (DDNP Analogs): Novel Diagnostic and Therapeutic Tools in Alzh eimer's Disease.", Molecular Imaging and Biology, 2003, 5 , P.404-417

^ Patent Document 9: Zhi— Ping Zhuang et al., “Structure— Activity Relationship of Imidazo [l , 2-a] pyridines as Ligands for Detecting β-Amyloid Plaques in the Brain. ", J. Med. Chem, 2003, 46, p.237-243

 Non-Patent Document 10: W. E. Klunk et al., "Imaging brain amyloid in Alzheumer's disease w ith Pittsburgh Compound-B.", Ann. Neurol., 2004, 55, p.306-319

 Patent Document 11: Nicolaas P. L. G. VerhoefF et al "" In- Vivo Imaging of Alzheimer Dis ease β -Amyloid With [11C] SB-13 PET., American Journal of Geriatric Psychiatry, 2004, 12, p.584-595

 Disclosure of the invention

 Problems to be solved by the invention

[0009] As described above, various compounds have been disclosed as diagnostic imaging probes for amyloid and are being studied for clinical application.

As a result of experiments using normal mice, TZDM, IBOX, and m-I-SB-labeled compounds [ ¹² ¾] have all been transferred into the brain at 2 minutes after administration. These compounds show a tendency to accumulate gradually in the brain over time after administration, when clearance from normal tissues is not sufficient (Special Table 2005 _ 512945, Zhi-Ping) Zhuang et al, Nuclear Medicine and Biology, 2001, 28, p.887-894, HF Kung et al. J. Am. Chem. Soc "2001, 123, p.12740-12741). Otherwise, there is a problem that sufficient contrast cannot be obtained at the site of amyloid accumulation.The compound labeled with SB-13 with ["C] may have a clearance from normal tissues in experiments using rats. The force shown The clearance speed is not fast enough (Masahiro Ono et al., Nuclear Medicine and Biology, 2003, 30, ρ · 565_571).

[0010] On the other hand, IMPY and other compounds having an imidazopyridine skeleton have the following properties when they migrate into the brain after administration and accumulate in amyloid. Unlike the compounds described above, clearance from normal tissues to have excellent properties such as fast, there is a clear result of the experiments with ^[12 ¾ Hyoshikyi匕compound. However, IMPY is a compound that shows a positive result in a reverse mutation test, and in order to use this compound as an imaging diagnostic probe, it is necessary to pay sufficient attention to its dosage and dosage form. (International Publication No. 03/106439 Issue pamphlet)

 FDDNP has also been reported to be positive in the reverse mutation test. (International pamphlet No. 03/106439)

[0011] As a diagnostic imaging probe targeting amyloid, it has affinity for amyloid and maintains the excellent performance of IMPY such as sufficiently high clearance from normal tissue, while maintaining toxicity such as mutagenicity. Although it is preferred to use compounds that have been suppressed, no compounds with such performance are currently disclosed.

[0012] The present invention has been made in view of the above circumstances, and has a compound having affinity for amyloid, sufficiently high clearance from normal tissue, and reduced toxicity such as mutagenicity. Aimed to obtain.

 Means for solving the problem

[0013] The inventor has found that a compound group satisfying the above conditions can be obtained by using a compound having an imidazopyridine phenyl skeleton, in which oxygen is bonded to carbon of the phenyl group. Was completed.

That is, the present invention provides the following formula (1):

で表される化合物及びその塩、並びに前記式（1)で表される化合物又はその塩を配 合してなる低毒性アルツハイマー病診断剤である。 [0015] [Chemical 4]

And a low-toxicity diagnostic agent for Alzheimer's disease comprising a compound represented by the above formula (1) or a salt thereof.

In the formula (1), R ¹ is hydrogen, a hydroxyl group, a carboxyl group, a sulfate group, an amino group, a nitro group, a cyano group, an alkyl substituent having 1 to 4 carbon atoms, or an alkoxy substituent having 1 to 4 carbon atoms. More arbitrary groups can be selected. R ¹ is more preferably a hydroxyl group, a methyl substituent, or a methoxy substituent, preferably a hydroxyl group, an alkyl substituent having 1 to 4 carbon atoms, or an alkoxy substituent having 1 to 4 carbon atoms. Masle.

R ² can be any radioactive halogen ^{substituent, 18 F, 76 Br, 123} I, 124 I, 125 I or ¹³¹ preferably be used a halogen selected from I instrument ¹⁸ F, ⁷⁶ Select from Br, ¹²³ 1 or ¹²⁵ 1 It is more preferred to use a halogen, which is particularly preferred.

 M is an integer of 0-2.

[0017] Further, according to another aspect of the present invention, amyloid deposits comprising the compound represented by the formula (1) or a salt thereof and a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition for in vivo imaging is provided.

 According to still another aspect of the present invention, there is provided a compound represented by the formula (1) or a salt thereof used for pharmaceutical use.

 According to still another aspect of the present invention, there is provided a compound represented by the formula (1) or a salt thereof for use in in vivo imaging of amyloid deposition.

 According to still another aspect of the present invention, (a) administering a detectable amount of the compound represented by the formula (1) or a salt thereof;

 (b) detecting binding of said compound or salt thereof to amyloid deposits in a patient, and a method for detecting amyloid deposits in a patient in vivo, comprising:

 According to a preferred embodiment of the present invention, the step (b) is performed by PET or SPECT imaging.

 [0018] According to another aspect of the present invention, the following formula (2):

[0019] [Chemical 5]

[0020] and a salt thereof are provided.

In the formula (2), R ³ is hydrogen, a hydroxyl group, a carboxyl group, a sulfate group, an amino group, a nitro group, a cyano group, an alkyl substituent having 1 to 4 carbon atoms, or an alkoxy substituent having 1 to 4 carbon atoms. More arbitrary groups can be selected. R ³ is more preferably a hydroxyl group, a methyl substituent, or a methoxy substituent, preferably a hydroxyl group, an alkyl substituent having 1 to 4 carbon atoms, or an alkoxy substituent having 1 to 4 carbon atoms. Masle.

[0022] R ⁴ may be a group selected from a non-radioactive halogen substituent, a methanesulfonic acid substituent, a trifluoromethanesulfonic acid substituent, or an aromatic sulfonic acid substituent. As the non-radioactive halogen substituent, a halogen that can be a target in a nucleophilic substitution reaction using radioactive fluorine can be used, and preferably iodine or bromine can be used.

 M is an integer of 0-2.

 The invention's effect

 [0023] According to the present invention, it is possible to obtain a compound and a low-toxicity Alzheimer's disease diagnostic agent having affinity for amyloid, sufficiently high clearance from normal tissues, and suppressed toxicity such as mutagenicity. It has become possible.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0024] In the following, taking 6-methoxy-2- (4 '-(3 "_para-toluenesulfonyloxypropoxy) phenyl] imidazo [1, 2_a] pyridine as an example, the radioactivity according to one embodiment of the present invention A method for synthesizing a precursor compound of a halogen-labeled compound will be described.

 [0025] First, 2_bromo_3-methoxypyridine is reacted with yowi-methinole in the presence of sodium methoxide to synthesize 2_bromo_3-methoxypyridine. Next, nitration with a mixed acid of concentrated sulfuric acid and concentrated nitric acid was performed, and after conversion to 2_bromo_3 methoxy_6_nitropyridine, reductive elimination of the bromo group by palladium carbon and reduction of the nitro group To synthesize 2_amino-5-methoxypyridine (FIG. 1, steps:! To 3). In these series of reactions, the reaction conditions can be set according to standard methods, for example, the method described in the literature (Joseph G. Lombardino, Journal of Medicinal Chemistry, 1981, 24, p. 39_42).

 Separately, 4′-hydroxyacetophenone and cupric bromide are reacted to synthesize 2-promo 4′-hydroxyacetophenone (FIG. 1, step 4). The reaction conditions at this time can be carried out according to a conventional method, for example, a method described in literature (King, L. Carroll and Ostrum, G. Kenneth, Journal of Organic Chemistry, 1964, 29 (12), p. 3459_3461).

 [0027] Next, the 2 bromo 4'-hydroxyacetophenone synthesized above and 2 amino-5-methoxypyridine were reacted with each other to produce 2- (4'-hydroxyphenyl) 1-6-methoxyimidazo [1, 2 a] Pyridine is synthesized (Figure 1, Step 5). This process can be performed as follows.

[0028] First, 2_bromo_4, monohydroxyacetophenone and 2-amino_5 methoxypyridine When dissolved in an inert solvent such as cetonitrile and allowed to react at reflux temperature for 2-6 hours, 2- (4, -hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine hydrobromide To form a white precipitate. As the inert solvent at this time, in addition to acetonitrile, a solvent usually used in the same reaction such as methanol or acetone can be used. The reaction temperature is not particularly limited as long as it can be refluxed. For example, when acetonitrile is used as a solvent, the reaction temperature can be 90 ° C. It should be noted that the amount of the solvent used is sufficient if it is sufficient for the reaction. However, if it is too much, it is impossible to obtain a precipitate of the reaction product, so care must be taken. For example, when 2_bromo_4′-hydroxyacetophenone equivalent to lOmmol is used for the reaction, a solvent of about 40 to 50 mL may be used.

 [0029] Next, the reaction solution is filtered and the precipitate is filtered off. Then, the white precipitate is suspended in a methanol / water mixture (1: 1), and then a saturated sodium bicarbonate aqueous solution is suspended in this precipitate. If it is added so that it becomes a large square IJ, 2_ (4,1hydroxyphenyl) 1-6-methoxyimidazo [1,2,2-a] pyridine is liberated and precipitation occurs. By filtering this newly generated precipitate, 2- (4, -hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine, which is the target product of this step, can be obtained as crystals. it can. The amount of the water / methanol mixed solution is not particularly limited as long as it is sufficient for the reaction. However, if it is too much, caution is required because it will hinder the precipitation of crystals. For example, if 2-bromo-4'-hydroxyacetophenone equivalent to lOmmol is used, a water / methanol mixture of about 40 to: OOmL may be used. Further, the amount of sodium bicarbonate is not particularly limited if it is a large excess with respect to the precipitate as a reaction substrate. For example, in the case of reacting under the above conditions, about 25 mL of saturated sodium bicarbonate Add an aqueous solution to the reaction solution.

[0030] Next, the synthesized 2_ (4, monohydroxyphenyl) _6-methoxyimidazo [1,2, _a] pyridine and 1,3_propanediol monoparatoluenesulfonate were added to tetrahydrofuran, N, N — Dissolve in a mixed solution of dimethylformamide, add triphenylphosphine and diisopropylpropyl dicarboxylate to this, and perform Mitsunobu reaction, which is the target product 6-methoxy-2-[4 '-(3 "_ P-toluenesulfonyloxypropoxy) phenyl] imidazo [1,2_a] pyridine can be obtained (Fig. 1, step 7), 1,3_propanedionomonomononaphthenosenosulfonate f as an auxiliary material. f row literature (Abderrahim Bouzide and Gilles Sauv e, Organic Letters, 2002, 4 (14), ρ · 2329_2332 ·), and can be easily synthesized (Fig. 1, step 6). Typically, it may be used in a molar ratio of about 2-fold with respect to 2- (4'-hydroxyphenyl) -6-methoxyimidazo [1, 2_a] pyridine, which is a reaction substrate. The amounts of triphenylphosphine and diisopropylazodicarboxylate are the same as those of 1,3_propanediol monoparatoluene sulfonate, which is typically an auxiliary material, according to general Mitsunobu reaction conditions. About a mole may be used.

 [0031] The compound in which the 6-position is a hydroxy substituent is obtained by adding boron tribromide or the like to 2_ (4'-hydroxyphenyl) _6-methoxyimidazo [1,2_a] pyridine obtained in Step 5 above. After the demethylation reaction is performed, the 6-position hydroxyl group is protected with a tetrahydropyranyl group, etc., and then the reaction in Step 7 is performed, and finally the 6-position protection group is deprotected. That power S. In addition, compounds in which the substituent bonded to the carbon at the 6-position is a methyl substituent or an ethoxy substituent are substituted with 2-amino-5-methylpyridine and 2-amino-5-methoxypyridine in Step 4, respectively. —Imidazo [1, 2—a] Compounds with different substituent positions in the pyridine ring, for example, compounds having a methyl substituent or a methoxy substituent bonded to the 8-position carbon Instead of 2 amino-5-methoxypyridine in step 4, use 2 amino-3 methylpyridine and 2 amino-3-methoxypyridine, respectively.

[0032] Next, 2- [4,-(3 "-[ ¹⁸ F] fluoropropoxy) phenyl] -6-methoxyimidazo [1,2, -a] pyridine is taken as an example in accordance with the present invention. A method for producing a radiohalogen-labeled compound will be described.

[0033] 2- [4 '- (3 "- [18 F] Full O b propoxy) phenyl] - In 6-methoxy-imidazo [1, 2 _ a] pyridine, first, a phase transfer catalyst ^[18 F ] A mixture containing fluoride ion and potassium ion is obtained [ ¹⁸ F] fluoride ion can be obtained by a known method, for example, by proton irradiation with H ¹⁸ O concentrated water as a target, obtain

 2

That power S. At this time, [ ¹⁸ F] fluoride ions are present in the target H ¹⁸⁰ concentrated water.

 2

Exist. The H ¹⁸⁰ concentrated water containing [ ¹⁸ F] fluoride ions is passed through an anion exchange column.

 2

Liquid is adsorbed and collected on the column, and separated from H ¹⁸⁰ concentrated water. Then the

2 A mixture containing a phase transfer catalyst, [ ¹⁸ F] fluoride ions and potassium ions is obtained by flowing potassium carbonate solution through the column to elute the [ ¹⁸ F] fluoride ions and adding a phase transfer catalyst to dryness. Can be obtained.

[0034] Here, as the phase transfer catalyst, various compounds having a property of forming an inclusion with [ ¹⁸ F] fluoride ion can be used. Specifically, various compounds used in the production of radioactive fluorine-labeled organic compounds can be used, and 18-crown-6-ether and other various aminopolyethers can be used. . As the most preferable mode, Talibufix 222 (trade name, manufactured by Merck & Co., Inc.) can be used.

[0035] Next, a dimethylformamide solution of 6-methoxy-1,2- [4,-(3 "_paratoluenesulfonyloxypropoxy) phenyl] imidazo [1,2_a] pyridine, which is a labeling precursor, was prepared and 2- [4 '-(3 "-] by carrying out the nucleophilic substitution reaction under the reaction conditions in addition to the mixture containing the phase transfer catalyst, [ ¹⁸ F] fluoride ion and potassium ion prepared in [ ¹⁸ F] Fluoropropoxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine is synthesized. The reaction conditions can be set according to the conditions in other radiofluorinated compounds such as 2- [ ¹⁸ F] fluoro-2-deoxy-D-glucose. For example, the reaction solution can be used under the condition of 90 to 130 ° C for 5 to 10 minutes.

[0036] The synthesis of other radiohalogen-labeled compounds can be performed by appropriately selecting a labeling precursor and a radiohalogen to be used, and giving reaction conditions according to known methods. For example, the synthesis of 2— [4, — (3 ,, — [ ¹² ¾ odopropoxy) phenyl] — 6-methoxymidazo [1, 2—a] pyridine can be synthesized using 2- [4 ′ 3 "- black port propoxy) Hue sulfonyl] - 6-methoxy-imidazo [1, 2 _a] Yore ,, acetone or methanol in a solvent of pyridine, be obtained by metathesis reaction with Na ^[123 I] it can.

[0037] The diagnostic agent according to the present invention, like other generally known radioactive diagnostic agents, is water or physiological saline or Ringer's solution in which the radiohalogen-labeled compound according to the present invention is adjusted to an appropriate pH as required. It can be prepared as a liquid blended with the above. In this case, the concentration of the present compound needs to be lower than the concentration at which the stability of the blended present compound is obtained. The dose of the compound should be sufficient to image the distribution of the administered drug There is no particular limitation as long as the concentration is high. For example, in the case of an iodine 123-labeled compound and a fluorine-18-labeled compound, it can be used by intravenous administration or local administration of about 50 to 600 MBq per adult with a body weight of 60 kg. The distribution of the administered drug can be imaged by a known method. For example, in the case of iodine-123 labeled compound, it can be imaged using a SPECT apparatus, and in the case of fluorine-18-labeled compound, it can be imaged using a PET apparatus. . Example

 [0038] Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Comparative Examples, but the contents of the present invention are not limited thereto.

 In the following examples, the names of the respective compounds were defined as shown in Table 1.

[0039] [Table 1]

[0040] (Reference Example 1) 2_ [4 '_ (3 "_fluoropropoxy) phenyl] -6 methoxyimidazo [1,

 Synthesis of 2_a] pyridine (non-radioactive fluorinated product)

 [0041] As a sample for investigating the affinity, lipophilicity and mutagenicity of the compound of the present invention to amyloid, 2- [4 '-(3 "-fluoropropoxy) phenyl] -6 methoxy A non-radioactive fluorinated product of imidazo [1,2-a] pyridine was synthesized.

[0042] 100 · 0 g of 2 bromo 3 hydroxypyridine (equivalent to 0.575 mol) was dissolved in 310 mL of dimethyl sulfoxide, and 575 mL of lmol / L sodium methoxide / methanol solution (equivalent to 0.575 mol) was added thereto. The reaction solution was heated to 90 ° C. and methanol was distilled off. After cooling the reaction solution to 10 ° C or lower, 93.9 g (corresponding to 0.662 mol) of yowi-methyl was added and stirred at room temperature for 20.5 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted twice with black mouth form. The combined black mouth form layer was washed with lmol / L sodium hydroxide and then washed with saturated saline solution. After washing twice and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 6-4 g (corresponding to 0.348 mol) of 2-promo-3-methoxypyridine (FIG. 2, step 1).

[0043] After cooling 262 mL of concentrated sulfuric acid to 2 ° C, carefully adding 262 mL of 90% nitric acid,

 2_Bromo_3-methoxypyridine 65.3 g (corresponding to 0.347 mmol) was carefully added. The reaction mixture was stirred in an ice bath for 10 minutes, then stirred at room temperature for 30 minutes, further heated to 55 ° C and stirred for 1.5 hours. The reaction solution was cooled to room temperature and then poured into ice in small portions to form a precipitate. The precipitate was collected by filtration and washed with water. This was dried under reduced pressure in the presence of diphosphorus pentoxide to obtain 55.7 g (corresponding to 0.239 mol) of 2-bromo-1-methoxy-6-nitropyridine (FIG. 2, step 2).

 [0044] 2_Bromo_3-methoxy_6_nitropyridine 55.6 g (corresponding to 0.239 mol) was dissolved in 1700 mL of ethanol, and under an argon stream10. /. After adding 37.3 g of palladium on carbon (50% wet), 283 mL of hydrazine monohydrate was added dropwise. The reaction mixture was heated to reflux for 70 minutes, and then the reaction solution was cooled to room temperature and palladium carbon was filtered. The filtrate was washed with ethanol, and the washing solution was combined with the filtrate. The solution was concentrated under reduced pressure, water (1300 mL) and concentrated aqueous ammonia (130 mL) were added, and the mixture was extracted eight times with black mouth form. The combined chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was distilled under reduced pressure to give 2 · 2 g of 2-amino-5-methoxypyridine (corresponding to 0.211 mol). Obtained (FIG. 2, step 3).

 [0045] 50 mL of ethyl acetate was suspended in 28.17 g (corresponding to 126 mmol) of cupric bromide, and 8 · 18 g (corresponding to 60. Ommol) of 4'-hydroxyacetophenone was suspended in 50 mL of ethyl acetate. A solution dissolved in 50 mL of mouth form was collected and heated to reflux. After 5 hours, the reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, the activated carbon was removed and the color was removed, and then the solution was filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (eluent: chloroform / methanol = 20/1) and recrystallized from ethyl acetate / petroleum ether, 2_bromo_4 7.25 g (corresponding to 33.7 mmol) of '-hydroxyacetophenone was obtained. (Figure 2, Step 4).

[0046] 2.15 g of 2-bromo-1,4-hydroxyacetophenone (corresponding to 10. Ommol) and 1.25 g of 2-amino-1-methoxypyridine (10. Ommol of wood) were dissolved in 50 mL of acetonitrile. The mixture was heated to reflux for 3.5 hours in an oil bath at 90 ° C. After completion of the reaction, the reaction solution is cooled to room temperature, After filtering off, it was washed with acetonitrile and dried under reduced pressure. The obtained crude crystals are water

After suspending in a 40 mL-methanol 40 mL mixture, about 20 mL of a saturated sodium bicarbonate solution was added thereto, and the mixture was shaken for 5 minutes using an ultrasonic cleaner. From the resulting mixture, the precipitate was filtered off, washed well with water, dried under reduced pressure, and 2- (4'-hydroxyphenyl) _ 6 -methoxyimidazo [1,2, _a] pyridine 1.96 g ( 8. 16mmol equivalent) was obtained (Fig. 2, step 5)

[0047] 2_ (4'-hydroxyphenyl) _6-methoxyimidazo [1,2_a] pyridine 242mg (equivalent to 1 .Ommol) which had been thoroughly dried to remove water was dissolved in 10mL of N, N-dimethylformamide, To this was added 418 mg (equivalent to 3. Ommol) of potassium carbonate. 1-Bromo_3_fluoropropane 140 z L (equivalent to 1.5 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was poured into water and extracted three times with black mouth form. The combined black mouth form layer was washed once with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Recycle fraction of the obtained crude product ^ 1? 1 ^? 1 ^ Device 丄 〇-908 (Product name, manufactured by Nihon Analytical Industrial Co., Ltd.), Column: Two JAIGEL 2H (Product name, manufactured by Nihon Analytical Industrial Co., Ltd.) connected, mobile phase: Kuroguchi Holm) 2- [4 '-(3 "-fluoropropoxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine (hereinafter referred to as Compound 1) 189 mg (corresponding to 0.63 mmol) Obtained (Figure 2, step 6).

 [0048] The NMR measurement result (internal standard substance: tetramethylsilane) of the obtained compound was as follows.

 [0049] NMR apparatus used: JNM— ECP— 500 (manufactured by JEOL Ltd.)

— NMR (solvent: heavy chloroform, resonance frequency: 500MHz): δ 7.83-7.79 (m, 2Η), 7.64-7.63 (s, 1H), 7.56-7.54 (m, IH), 7.48-7.45 (m, IH), 6.95—6.92 (m, 2H), 6.93-6.90 (m, IH), 4.65 (dt, ² J = 47.0 Hz, J = 6.0 Hz, 2H), 4.11 (t, J = 6.0 H

 HF

z, 2H), 3.75 (s, 3H), 2.17 (dquint, ³ J = 25.9 Hz, J = 6.0 Hz, 2H).

 HF

[0050] ¹³ C_NMR (solvent: deuterium formaldehyde, resonance frequency: 125 MHz): δ 158.48, 149.06, 14 5.42, 142.64, 126.93, 126.80, 119.39, 117.22, 114.58, 108.31, 107.39, 80.66 (d, 'j = 164.6 Hz), 63.46 (d, ³ J = 5.8 Hz), 56.02, 30.33 (d, ² J = 20.2 Hz).

 CF CF CF

[0051] ¹⁹ F_NMR (solvent: heavy-mouthed form, resonance frequency: 470 MHz): δ -221.94 (tt, ² J = 47.0 Hz, ³ J = 25.9 Hz).

 HF

 [0052] (Reference Example 2) Synthesis of 2- [4,1 (3 "-fluoropropoxy) phenyl] -6-hydroxyimidazo [1,2-a] pyridine (non-radioactive fluorinated compound)

 [0053] 2_ [4 '_ (3 "_Fluoropropoxy) phenyl]-6-hydroxy was used as a sample for investigating the affinity, lipophilicity and mutagenicity of the compounds of the present invention for amyloid. A non-radioactive fluorinated compound of imidazo [1,2-a] pyridine was synthesized.

 [0054] 2_Bromo_ 3-hydroxypyridine 31. l lg (equivalent to 178. 88 mmol) was dissolved in 95.8 mL of dimethyl sulfoxide, and 89.9 mL of ImolZL sodium methoxide / methanol solution (equivalent to 89.9 mmol) ) Was added, and the reaction solution was heated to 90 ° C to distill off methanol. After cooling the reaction solution to 5 ° C or lower, 29.2 g (corresponding to 205.62 mmol) of yowi methinole was added and stirred at room temperature for 17 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted twice with black mouth form. The combined chloroform layer was washed with lmol / L sodium hydroxide, then washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2-promo 3-methoxypyridine. 20 · 74 g (corresponding to 110.31 mmol) were obtained (FIG. 3, step 1).

 [0055] 83 mL of concentrated sulfuric acid was cooled to -5 ° C, and 83 mL of 90% nitric acid was carefully added thereto, and then 20 · 69 g of 2-bromo-3-methoxypyridine (equivalent to 110.04 mmol) was added carefully. The reaction mixture was stirred in an ice bath for 5 minutes, then stirred at room temperature for 10 minutes, further heated to 55 ° C. and stirred for 1 hour. The reaction solution was cooled to room temperature and then poured into ice in small portions to form a precipitate. The precipitate was collected by filtration and washed with water. This was dried under reduced pressure in the presence of diphosphorus pentoxide to obtain 17-41 g (corresponding to 74.71 mmol) of 2-bromo-3-methoxy-6-ditropyridine (FIG. 3, step 2).

[0056] 17.36 g (equivalent to 74. 50 mmol) of 2_bromo_3-methoxy_6_nitropyridine was dissolved in 520 mL of ethanol, and 11.63 g of 10% palladium carbon (50% wet) was added under an argon stream. Thereafter, 88.4 mL of hydrazine monohydrate was added dropwise. The mixture was heated to reflux for 45 minutes, cooled to room temperature, palladium carbon was filtered, the filtrate was washed with ethanol, and the washing was combined with the filtrate. The solution was concentrated under reduced pressure, 402 mL of water and 38 mL of concentrated aqueous ammonia were added, and the mixture was extracted 8 times with black mouth form. The combined chloroform layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then distilled under reduced pressure to give 8.14 g of 2-amino-5-methoxypyridine (65. (Corresponding to 57 mmol) was obtained (Fig. 3, step 3).

 [0057] 4, 1-Benzoxylacetophenone 13 · 50g (equivalent to 59.66mmol) was dissolved in 1100mL of methanol and 34 · 52g of tetrabutyl butylammonium tribromide (71.59mmol equivalent) was added. And stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with water and then with saturated brine. The crude product obtained by drying the ethyl acetate layer over anhydrous sodium sulfate and concentrating under reduced pressure was purified by silica gel column chromatography (eluent: hexane Z salt 匕 methylene = 1/1). 13.38 g (corresponding to 43.84 mmol) of '-benzoyloxy_2-bromoacetophenone was obtained (Fig. 3, step 4).

 [0058] 4'-Benzoxyl-2-bromoacetophenone 13.33g (equivalent to 43.68mmol) and 2-amino-5-methoxypyridine 5.67g (equivalent to 45.67mmol) were dissolved in 481mL of ethanol. Heated to reflux for hours. After cooling the reaction solution, 6.64 g (equivalent to 79.09 mmol) of sodium hydrogen carbonate was added, and the reaction mixture was further heated to reflux for 4 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was dissolved in black mouth form and washed with water. After the chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 20/1). 2 (4,1 Benzoxylphenyl) 1 6-methoxyimidazo [1,2-a] pyridine 10 · 20 g (corresponding to 30.87 mmol) (FIG. 3, step 5).

 [0059] 2— (4 'Benzoxylphenyl) 6-methoxyimidazo [1, 2— a] pyridine (90.90 g (14.83 mmol equivalent)) that had been thoroughly dried to remove water was added to 245 mL Dissolved and cooled to 15 ° C. A solution obtained by dissolving 12.62 mL of boron tribromide (equivalent to 133.48 mmol) in 134 mL of dichloromethane was added dropwise thereto, and the mixture was warmed to room temperature and stirred for 17 hours. After completion of the reaction, the reaction mixture was ice-cooled, 668 mL of methanol was added, and the mixture was further stirred at room temperature for 3 hours, and then the reaction mixture was concentrated under reduced pressure. The crude product thus obtained was repulped with 290 mL of black mouth form and 29 mL of methanol, and the precipitate was filtered off. The precipitate separated by filtration was washed with black mouth form, dried under reduced pressure, and 2- (4'-hydroxyphenyl) _6-hydroxyimidazo [1,2, _a] pyridine (3.00 g, equivalent to 13.28 mmol) (Figure 3, Step 6).

[0060] 2_ (4,1hydroxyphenyl) 1-6-hydroxyimidazo [1, 2 _a] pyridine 2.98 g (equivalent to 13.17 mmol) was dissolved in dimethylformamide 114 mL, and then potassium carbonate 2.19 g (corresponding to 15.8 mmol) was added and cooled to 4 ° C. To this was added dropwise a solution of methoxymethyl chloride 1 · 59 mL (corresponding to 21.08 mmol) in dimethylformamide 4.8 mL, and the reaction solution was warmed to room temperature and stirred for 21 hours. After completion of the reaction, the reaction solution was concentrated, and 57 mL of chloroform and 57 mL of methanol were added thereto for repulping, followed by filtration to separate the precipitate and the filtrate. The precipitate was washed with 114 mL of a black form-methanol mixture (1: 1), and the filtrates were combined and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1 → 5/1) and 2- (4'-hydroxyphenyl) _4-methoxymethyl _ 6 —Methoxymethoxyimidazo [1,2, _a] pyridinum chloride 2.03 g (5.78 mmol) was obtained (FIG. 3, step 7).

 [0061] 2- (4,1-hydroxyphenyl) _4-methoxymethyl-6-methoxymethoxyimidazo [1, 2 _a] pyridinum chloride 2.01 g (corresponding to 5.73 mmol) in 83.6 mL of dimethylformamide After dissolution, 3.17 g (corresponding to 22.92 mmol) of potassium carbonate and 1.62 g (corresponding to ll. 46 mmol) of 1_bromo_3_fluoropropane were added and stirred overnight at room temperature. After completion of the reaction, the reaction solution was poured into water, sodium chloride was added, and the mixture was extracted twice with black mouth form while salting out. The combined black mouth form layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crude product was subjected to silica gel column chromatography (eluent: black mouth form / methanol = 10/1). → 5/1), 2— [4,1 (3 ”-Fluoropropoxy) phenol] -4-methoxymethyl-6-methoxymethoxyimidazo [1,2, —a] pyridinium Muclide 1 • 95 g (corresponding to 4.57 mmol) was obtained (Fig. 3, step 8).

 [0062] 2- [4 '-(3 "-Fluoropropoxy) phenyl] -4-methoxymethyl-6-methoxymethoxyimidazo [1,2, -a] pyridinum chloride 1 · 93g (corresponding to 4.53mmol) ) Was dissolved in 29 mL of methanol, 0.95 mL of concentrated hydrochloric acid was added, and the mixture was heated to reflux for 2 hours.The reaction mixture was cooled, then poured into water and poured into water to form sodium chloride. The combined chloroform layer was dried over anhydrous magnesium sulfate and concentrated, and the resulting crude product was subjected to silica gel column chromatography (eluent: black mouth form / methanol = 10/1 → 5/1). 2_ [4, _ (3 "_ Fluoropropoxy) phenyl] -6-methoxymethoxyimidazo [1,2_a] pyridine 1.22g (equivalent to 3.68mmol) ( Figure 3, Step 9).

[0063] 2- [4 '-(3 "_Fluoropropoxy) phenyl]-6-methoxymethoxyimidazo [1, 2- a] Pyridine 1 · 18 g (corresponding to 3.57 mmol) was dissolved in 29 mL of isopropyl alcohol, and 0.59 mL of concentrated hydrochloric acid was added and heated to reflux for 23 hours. After cooling the reaction solution, it was poured into water and extracted twice with black mouth form while adding sodium chloride and praying for salt. The combined chromatophore layers were dried over anhydrous magnesium sulfate, and the resulting crude product was purified by silica gel column chromatography (eluent: chromatoform Zmethanol = 10Zl). _ (3 "_fluoropropoxy) phenyl] _6-hydroxyimidazo [1,2_a] pyridine (hereinafter referred to as compound 2) 481 mg (corresponding to l.68 mmol) was obtained (FIG. 3, step 10).

[0064] The NMR measurement results (internal standard substance: dimethyl sulfoxide) of the obtained compound were as follows.

 [0065] NMR apparatus used: JNM—GSX—270 (manufactured by JEOL Ltd.)

iH—NMR (solvent: deuterated dimethyl sulfoxide, resonance frequency: 270 MHz): δ 8.52 (s, 2 H), 8.30-8.25 (m, 1H), 7.85-7.79 (m, 1H), 7.67-7.62 (m, 1H ), 7.22-7.16 (m, 2H), 5.64 (s, 1H), 4.62 (dt, ² J = 47.0 Hz, J = 5.9 Hz, 2H), 4.17 (t, J = 5.9 Hz,

 HF

2H), 2.14 (dquint, ³ J = 26.2 Hz, J = 5.9 Hz, 2H).

 HF

 [0066] (Reference Example 3) 2— [4,1 (3 ”-Fluoropropoxy) phenyl] imidazo [1, 2, a] pyridine

 Synthesis of (non-radioactive fluorinated product)

[0067] As a sample for examining the affinity, lipophilicity and mutagenicity of the compound of the present invention for amyloid, 2- [4,1 (3 "-fluoropropoxy) phenyl] imidazo [1, 2 — We synthesized a non-radioactive fluorinated product of a] pyridine.

 [0068] 50 mL of ethyl acetate is suspended in 28.17 g (corresponding to 126 mmol) of cupric bromide, and 8 · 18 g (corresponding to 60. Ommol) of 4'-hydroxyacetophenone is suspended in 50 mL of ethyl acetate. A solution dissolved in 50 mL of mouth form was collected and heated to reflux. After 5 hours, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and decolorized by adding activated carbon, and then the solution was filtered and concentrated. The obtained crude product was purified by flash silica gel column chromatography (eluent: chloroform / methanol = 20/1) and recrystallized from ethyl acetate-petroleum ether, 2_bromo_4, 7.25 g (corresponding to 33.7 mmol) of monohydroxyacetophenone was obtained. (Figure 4, step 1).

[0069] 2_Bromo_4'-hydroxyacetophenone 649mg (equivalent to 3. Ommol) and 2-aminominopyridy 285 mg (equivalent to 3. Ommol) was dissolved in 20 mL of acetonitrile and heated to reflux in an oil bath at 110 ° C for 1 hour. After cooling the reaction solution to room temperature, 254 mg (equivalent to 5.4 mmol) of sodium hydrogen carbonate was added, and the mixture was further heated to reflux in a 100 ° C. oil bath for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, the precipitate was filtered off, and the obtained precipitate was washed with acetonitrile and water. This was dried under reduced pressure to obtain 405 mg (corresponding to 1 .9 mmol) of 2_ (4′-hydroxyphenyl) imidazo [1,2-a] pyridine (FIG. 4, step 2).

[0070] 2_ (4'-Hydroxyphenyl) imidazo [1,2, _a] pyridine (398 mg, equivalent to 1.89 mmol), which had been thoroughly dried to remove water, was dissolved in 15 mL of N, N dimethylformamide. To this was added 788 mg of potassium carbonate (corresponding to 5.7 mmol). 1_Bromo_3_fluorinated propane 260 x L (equivalent to 2.8 mmol) was added thereto, and the mixture was stirred at room temperature for 20.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted three times with black mouth form. The combined black mouth form layer was washed with water and saturated Japanese salt water, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product is recycled by preparative HPLC (HPLC apparatus: LC 908 (product name, manufactured by Nihon Analytical Industrial Co., Ltd.)), column: JAIGEL 2H (product name, manufactured by Nihon Analytical Industrial Co., Ltd.), two linked, mobile phase: 2- [4 '-(3 "-fluoropropoxy) phenyl] imidazo [1,2-a] pyridine (hereinafter referred to as Compound 3) 264mg (corresponding to 0.998mmol) (Figure 4, step 3).

 [0071] NMR measurement results (internal standard substance: tetramethylsilane) were as follows.

[0072] NMR apparatus used: JNM— ECP— 500 (manufactured by JEOL Ltd.)

¹ H—NMR (solvent: heavy chloroform, resonance frequency: 500 MHz): δ 8.09 (dt, J = 6.9, 1.

2 Hz, 1H), 7.90-7.86 (m, 2H), 7.76 (d, J = 0.7 Hz, 1H), 7.62-7.59 (m, 1H), 7.

14 (ddd, J = 9.1, 6.7, 1.2 Hz, 1H), 6.99—6.95 (m, 2H), 6.75 (dt, J = 6.7, 1.2 Hz,

1H), 4.67 (dt, ² J = 47.0 Hz, J = 6.0 Hz, 2H), 4.14 (t, J = 6.0 Hz, 2H), 2.19 (d

 HF

 quint., J = 25.9 Hz, J = 6.0 Hz, 2H).

 HF

[0073] ¹³ C_NMR (solvent: deuterium form, resonance frequency: 125 MHz): δ 158.74, 145.68, 145 • 61, 127.29, 126.67, 125.42, 124.41, 117.29, 114.69, 112.21, 107.21, 80.73 (d,

 c

= 164.6 Hz), 63.53 (d, ³ J = 5.3 Hz), 30.42 (d, ² J = 20.2 Hz).

 F CF CF

[0074] ¹⁹ F_NMR (solvent: deuterated form, resonance frequency: 470 MHz): δ -222.04 (dd, ² J = 4 7.0 Hz, ³ J = 25.9 Hz).

 HF

 [0075] (Reference Example 4) 2— [4,1 (3 "Fluoropropoxy) phenyl] 6 Synthesis of [1, 2 a] pyridine (non-radioactive fluorinated compound)

[0076] For the purpose of creating a calculation formula used for calculating logP of the compound according to the present invention, 2_ [4 '

 HPLC

 -A non-radioactive fluorinated compound of (3 "_fluoropropoxy) phenyl] _ 6 _odoimidazo [1,2_a] pyridine was synthesized.

 [0077] Add 50 mL of ethyl acetate to 28.17 g (corresponding to 126 mmol) of cupric bromide and suspend it, and then add 8.18 g (corresponding to 60. Ommol) of 4'-hydroxyacetophenone 50 mL of ethyl acetate 50 mL chloroform 50 mL The mixture was added and heated to reflux. After 5 hours, the reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and decolorized by adding activated carbon, and then the solution was filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (eluent: chloroform / methanol = 20/1) and recrystallized from ethyl acetate petroleum ether. 7-25 g (corresponding to 33.7 mmol) of '-hydroxyacetophenone was obtained (Fig. 5, step 1).

 [0078] 441 mg (corresponding to 2. Ommol) of bromo-4, monohydroxyacetophenone and 449 mg of 2-amino-5-iodopyridine (corresponding to 2. Ommol) are dissolved in 15 mL of acetonitrile and heated in an oil bath at 110 ° C for 5 hours. Refluxed. After completion of the reaction, the reaction solution was cooled to room temperature, and the precipitate was filtered off, washed with acetonitrile, and dried under reduced pressure. The obtained crude crystals were suspended in a mixture of water (10 mL) and methanol (10 mL), about 10 mL of a saturated sodium bicarbonate solution was added thereto, and the mixture was shaken with an ultrasonic cleaner for 5 minutes. From the resulting mixture, the precipitate was filtered off, washed well with water, and dried under reduced pressure to give 526 mg of 2- (4'-hydroxyphenyl) -6 odoimidazo [1,2, _a] pyridine (corresponding to 56 mmol). Obtained (FIG. 5, step 2).

[0079] 2_ (4'-Hydroxyphenyl) _6 _Edoimidazo [1, 2 _ &] pyridine 67711 ^ (corresponding to 2. Ommol), which was thoroughly dried and dehydrated, was dissolved in 25 mL of N, N dimethylformamide, To this was added 831 mg (equivalent to 6. Ommol) of potassium carbonate. To this was added 1-bromo-1-3-funoleopropane 275 z L (corresponding to 3. Ommol), and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was poured into water and extracted three times with black mouth form. The combined chloroform layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Gain The resulting crude product was purified by flash silica gel column chromatography (eluent: chlorophenol), and further recycled preparative HPLC (HPLC apparatus: LC-908 (product name, manufactured by Japan Analytical Industries, Ltd.), column: JAIGEL 2 _ [4, _ (3 "_Fluoropropoxy) phenyl] _ 6 _ 2H (Product name, manufactured by Nippon Analytical Industrial Co., Ltd.) This gave 349 mg (equivalent to 0.881 mmol) of pseudoimidazo [1, 2 _a] pyridine (Fig. 5, step 3).

 [0080] NMR measurement results (internal standard substance: tetramethylsilane) of 2_ [4 '_ (3 "_Fluoropropoxy) phenyl] _6_phoidimidazo [1,2-a] pyridine obtained are as follows: It was as follows.

 [0081] NMR apparatus used: JNM— ECP— 500 (manufactured by JEOL Ltd.)

iH—NMR (solvent: heavy chloroform, resonance frequency: 500 MHz): δ 8.37-8.35 (m, 1H), 7.88-7.84 (m, 2H), 7.72 (s, 1H), 7.42-7.39 (m, 1H ), 7.32 (dd, J = 9.4, 1.6 Hz, 1H), 6.99-6.96 (m, 2H), 4.67 (dt, ² J = 47.0 Hz, J = 6.0 Hz, 2H), 4.15 (t, J =

 HF

6.0 Hz, 2H), 2.20 (dquint, ³ J = 25.9 Hz, J = 6.0 Hz, 2H).

 HF

[0082] ¹³ C—NMR (solvent: deuterated form, resonance frequency: 125 MHz): δ 159.01, 146.23, 144.16, 132.36, 130.28, 127.42, 126.05, 118.31, 114.77, 106.90, 80.72 (d, 'j = 164.

 CF

6 Hz), 74.80, 63.57 (d, ³ J = 5.3 Hz), 30.42 (d, ² J = 20.2 Hz).

 CF CF

[0083] ¹⁹ F—NMR (solvent: heavy chloroform, resonance frequency: 470 MHz): 5 -222.09 (dd, ² J = 4

 HF

7.0 Hz, ³ J = 25.9 Hz).

 HF

 [0084] (Reference Example 5) Synthesis of 2- (4, -hydroxyphenyl) -6-odoimidazo [1,2, -a] pyridine

 [0085] For the purpose of preparing a calculation formula used for calculating logP of the compound according to the present invention, 2- (4 '

 HPLC

 —Hydroxyphenyl) _6 _Edoimidazo [1, 2_a] pyridine non-radioactive fluorinated compound was synthesized.

[0086] Add 50 mL of ethyl acetate to 28.17 g (corresponding to 126 mmol) of cupric bromide and suspend it, and then add 8.18 g (corresponding to 60. Ommol) of 4'-hydroxyacetophenone in 50 mL of ethyl acetate. A mixture of 50 ml of roloform was added and heated to reflux. After 5 hours, the reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. Dissolve the residue in ethyl acetate and add activated carbon to remove. After color operation, the solution was filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (eluent: chloroform / methanol = 20/1), and recrystallized from ethyl acetate-petroleum ether, 2-bromo- 4.25 g (corresponding to 33.7 mmol) of 4′-hydroxyacetophenone was obtained (FIG. 6, step 1).

 [0087] 441 mg (corresponding to 2. Ommol) of 2-bromo-1 4'-hydroxyacetophenone and 449 mg (corresponding to 2. Ommol) of 2-amino-1-sodium pyridine were dissolved in 15 mL of acetonitrile. The mixture was heated to reflux for 5 hours in a C oil bath. After completion of the reaction, the reaction solution was cooled to room temperature, and the precipitate was filtered off, washed with acetonitrile, and dried under reduced pressure. The obtained crude crystals were suspended in a mixture of 10 mL of water and 10 mL of methanol, about 10 mL of a saturated sodium bicarbonate solution was added thereto, and the mixture was shaken with an ultrasonic cleaner for 5 minutes. The resulting mixture was filtered off, washed well with water and dried under reduced pressure to give 526 mg of 2- (4'-hydroxyphenyl) _6 _odoimidazo [1,2, _a] pyridine (corresponding to .56 mmol). Obtained (FIG. 6, step 2).

 [0088] The results of NMR measurement (internal standard substance: dimethyl sulfoxide) of the obtained 2- (4'-hydroxyphenyl) -6-6-imidazo [1,2-a] pyridine were as follows. .

 [0089] NMR apparatus used: JNM— ECP— 500 (manufactured by JEOL Ltd.)

 iH—NMR (solvent: heavy dimethyl sulfoxide, resonance frequency: 500 MHz): 5 8.86-8.84 (m, 1H), 8.14 (s, 1H), 7.78-7.74 (m, 2H), 7.40-7.35 (m, 2H) 6.86—6.82 (m, 2H).

[0090] ¹³ C—NMR (solvent: deuterated dimethyl sulfoxide, resonance frequency: 125 MHz): δ 158.08, 14 5.87, 143.87, 132.48, 131.72, 127.67, 124.99, 118.14, 116.14, 108.02, 75.85.

[0091] (Reference Example 6) [ ¹² ¾— 2— (4,1 (3 "-Fluoropropoxy) Synthesis of 6-Yodoimidazo [1,2_a] pyridine

[0092] For the purpose of creating a calculation formula used to calculate LogP, the following steps are followed: [ ¹² ¾-2

 HPLC

 -(4, _ (3 "_Fluoropropoxy) phenyl 1-6 odoimidazo [1, 2_a] pyridine was synthesized.

[0093] 50 mL of ethyl acetate was suspended in 28.17 g (corresponding to 126 mmol) of cupric bromide, and 8.18 g (corresponding to 60. Ommol) of 4'-hydroxyacetophenone was suspended in 50 mL of ethyl acetate. A solution dissolved in 50 mL of mouth form was collected and heated to reflux. After 5 hours, the reaction mixture The mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and decolorized by adding activated carbon, and then the solution was filtered and concentrated. The obtained crude product was purified by flash silica gel column chromatography (eluent: chloroform / methanol = 20/1), and recrystallized from ethyl acetate-petroleum ether, 2_bromo _4 ' —Hydroxyacetophenone 7.25 g (corresponding to 33.7 mmol) was obtained (FIG. 7, step 1).

 [0094] 2.15 g (corresponding to 10. Ommol) of 2-bromo-1,4-hydroxyacetophenone and 1.74 g (10. Ommol of wood) of 2-amino-1,5-mol pyridine were dissolved in 50 mL of acetonitrile. The mixture was heated to reflux for 6 hours in an oil bath at 105 ° C. After completion of the reaction, the reaction solution was cooled to room temperature, the precipitate was filtered off, washed with acetonitrile, and dried under reduced pressure. The obtained crude crystals were suspended in a mixture of 20 mL of water and 20 mL of methanol, about 25 mL of a saturated sodium hydrogen carbonate solution was added thereto, and the mixture was shaken with an ultrasonic cleaner for 5 minutes. From the resulting mixture, the precipitate was filtered off, washed well with water, dried under reduced pressure, and 6_bromo_2_ (4'-hydroxyphenyl) imidazo [1,2-a] pyridine 2.41 g (8 (Equivalent to 32 mmol) was obtained (Fig. 7, step 2).

 [0095] 6-Bromo 2- (4'-hydroxyphenyl) imidazo after thoroughly drying to remove moisture

 [1,2-a] pyridine (290 mg, equivalent to 1 Ommol) was dissolved in N, N-dimethylformamide (10 mL), and potassium carbonate (413 mg, equivalent to 3. Ommol) was added thereto. 1-Bromo-3-fluoropropane 138 / i L (corresponding to 5 mmol) was added thereto, and the mixture was stirred at room temperature for 20.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted three times with black mouth form. The combined black mouth form layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Recycled preparative HPLC (HPLC equipment: LC-908 (product name, manufactured by Nippon Analytical Industrial Co., Ltd.), column: JAIGEL 2H (product name, manufactured by Nihon Analytical Industrial Co., Ltd.) Phase: 6_bromo_2_ [4, _ (3 "_fluoropropoxy) phenyl] imidazo [1,2_a] pyridine (302 mg, equivalent to 0.866 mmol) 7, step 3).

[0096] 6_Bromo_2_ [4 '_ (3 "_Fluoropropoxy) phenyl] imidazo [1,2_a] pyridin 85mg (equivalent to 0.24mmol) was dissolved in dioxan lOmL, After 2 mL of trichinoleamine was added, 185〃L (corresponding to 0.36 mmol) of bistributyltin and 20 mg (catalytic amount) of tetrakistriphenylphosphine palladium were added to this, and the reaction mixture was stirred at 90 ° C for 24 hours. After that, the solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC (eluent: hexane / ethyl acetate = 6/4). Furthermore, the obtained crude product was recycled by preparative HPLC (HPLC equipment: LC-908 (product name, manufactured by Nihon Analytical Industrial Co., Ltd.), column: JAIGEL 2H (product name, manufactured by Nihon Analytical Industrial Co., Ltd.). 6_tributylstannyl _2_ [4 '-(3 "_fluoropropoxy) feninore] imidazo [1, 2-a] pyridine 42mg (equivalent to 74.2 zmol) Obtained (FIG. 7, step 4).

 [0097] The result of NMR measurement of 6_tributylstannyl _2_ [4,-(3 "_fluoropropoxy) phenyl] imidazo [1, 2_a] pyridine (internal standard substance: tetramethylsilane) is It was as follows.

 [0098] NMR apparatus used: JNM- ECP-500 (manufactured by JEOL Ltd.)

 iH—NMR (solvent: heavy chloroform, resonance frequency: 500 MHz): δ 8.01-7.93 (m, IH), 7.91-7.87 (m, 2H), 7.75-7.74 (m, IH), 7.63-7.58 (m , IH), 7.20-7.11 (m, IH), 7.00-6.95 (m, 2H), 4.67 (dt, J = 47.0 Hz, J = 6.0 Hz, 2H), 4.15 (t, J = 6.0 H

 HF

 z, 2H), 2.20 (dquint, J = 26.1 Hz, J = 6.0 Hz, 2H), 1.64-1.47 (m, 6H), 1.39-1.

 HF

 31 (m, 6H), 1.19-1.04 (m, 6H), 0.91 (t, J = 7.2 Hz, 9H)

[0099] 6-tributylstannyl-2- [4,-(3 "-fluoropropoxy) phenyl] imidazo [1,2, -a] pyridine in methanol (concentration: lmg / mL) to 100 / iL, I mol / L hydrochloric acid 50 / iL, ^[125 1] sodium iodide 10 of 37~370MBq:. 100 / iL, 10 % (W / V) was added peroxide hydrogen 20 / L of the mixed solution to room temperature The sample was allowed to stand for 10 minutes, and then subjected to HP LC under the following conditions: [ ¹²⁵ 1] — 2— (4, 1 (3 ”-fluoropropoxy) phenol 6- odoimidazo [1, 2— a] Pyridine fraction was collected (FIG. 7, step 5).

 [0100] HPLC conditions:

 Column: Phenomenex Luna 〇18 (trade name,? 116 011½116, size: 4.6 150mm)

 Mobile phase: 0.1% Trifluoroacetic acid Z 0.1% Triacetoacetate containing acetonitrile = 8 0/20 → 0/100 (17 minutes)

 Flow rate: 1.0 mL / min

Detector: UV-visible absorptiometer (detection wavelength: 282nm) and radiation detector (raytes) t company STEFFI type)

[0101] A solution obtained by adding lOmL of water to the fraction was passed through a Sep-Pak C18 column (trade name: Sep-Pak (registered trademark) Light C18 Cartridges, Waters, packing amount of filler 130 mg). , [ ¹²⁵ 1] _ 2_ (4 '_ (3, _fluoropropoxy) phenyl_6 _ odomididazo [1, 2-a] pyridine was adsorbed and collected on the column. This column was washed with 1 mL of water. After that, ethanol (mL) was passed through to elute [ ¹² ¾-2- (4 '-(3 "-fluoropropoxy) phenyl-6-thiodoimidazo [1, 2_a] pyridine. The radioactivity was 37.5MBq immediately after synthesis, and the radiochemical purity was 96.5% by TLC analysis under the following conditions.

 [0102] TLC analysis conditions:

 TLC plate: RP—18F254 (product name, Merck)

 Developing phase: methanol / water = 20/1

 Detector: Bioimaging analyzer, BAS-2500 (Type: BAS-2500, manufactured by Fuji Photo Film Co., Ltd.)

[0103] (Reference Example 7) [ ¹²⁵ 1]-2-(4, -Hydroxyphenyl) -6 Synthesis of [1, 2-a] pyridine

[0104] For the purpose of creating the calculation formula used to calculate LogP, the following steps are followed: [ ¹²⁵ 1]

 HPLC

 —2— (4, 1-hydroxyphenyl) 6 pseudoimidazo [1, 2-a] pyridine was synthesized.

[0105] 50 mL of ethyl acetate is suspended in 28.17 g (corresponding to 126 mmol) of cupric bromide, and 8 · 18 g (corresponding to 60. Ommol) of 4'-hydroxyacetophenone is suspended in 50 mL of ethyl acetate. A solution dissolved in a 50 mL mixed solution was added and heated to reflux. After 5 hours, the reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and decolorized by adding activated carbon, and then the solution was filtered and concentrated. The obtained crude product was purified by flash silica gel column chromatography (eluent: chloroform / methanol = 20/1), and recrystallized from ethyl acetate-petroleum ether, 2_bromo _4 ' —Hydroxyacetophenone 7.25 g (corresponding to 33.7 mmol) was obtained (FIG. 8, step 1).

[0106] 2.15 g (corresponding to 10. Ommol) of 2-bromo-1,4-hydroxyacetophenone and 1.74 g (10. Ommol of wood) of 2-amino-1,5 ml of acetonitrinol , 105 ° C The mixture was heated to reflux in an oil bath for 6 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the precipitate was filtered off, washed with acetonitrile, and dried under reduced pressure. The obtained crude crystals were suspended in a mixture of 20 mL of water and 20 mL of methanol, and about 25 mL of a saturated sodium bicarbonate solution was added thereto, followed by shaking with an ultrasonic cleaner for 5 minutes. From the resulting mixture, the precipitate was filtered, washed well with water, dried under reduced pressure, and 6_bromo_2_ (4'-hydroxyphenyl) imidazo [1,2_a] pyridine 2.41 g (8 (Equivalent to 32 mmol) was obtained (Fig. 8, step 2).

[0107] 6_Bromo _2_ (4 '-hydroxyphenyl) imidazo [1, 2_a] pyridine 138 mg (equivalent to 0.47 mmol) was dissolved in 20 mL of dioxane, 2 mL of triethylamine was added, and then pistiblibutinoles 360 β L · (Corresponding to 0.771 mmol) and 20 mg (catalytic amount) of tetrakistriphenylphosphine palladium were added. After stirring the reaction mixture at 90 ° C. for 22 hours, the solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC (eluent: hexane / ethyl acetate = 1Z4). Furthermore, the obtained crude product is recycled by preparative HPLC (HPLC apparatus: LC_908 (product name, manufactured by Nihon Analytical Industrial), column: JAIGEL 2H (product name, manufactured by Nihon Analytical Industrial), Mobile phase: chloroform) to obtain 47 mg (equivalent to 94.9 / imol) of 6-tributylstannyl-2- (4, -hydroxyphenyl) imidazo [1,2-a] pyridine ( Figure 8, process 3).

[0108] 6 Tributylstannyl 2- (4, monohydroxyphenyl) imidazo [1, 2-a] pyridine in methanol (concentration: lmg / mL) 53 iL, lmol / L hydrochloric acid 50 / iL, 136MBq [ ¹² ¾ sodium iodide (capacity 40 / L), 10% (W / V) hydrogen peroxide 10 μL was added. The mixture was allowed to stand at 50 ° C for 10 minutes, and then subjected to HPLC under the same conditions as in Reference Example 6 [2- (4, monohydroxyphenyl) 6-odoimidazo [1, 2—a] The pyridine fraction was collected (Fig. 8, step 4).

[0109] A solution obtained by adding 10 mL of water to the relevant fraction was used as a reverse-phase column (trade name: Sep Pak (registered trademark, Waters 'Investmen' Limited) Light C18 Cartridges, Waters, Packing amount of packing material : 130 mg), [ ¹² ¾ _2_ (4, -hydroxyphenyl) _6_ odoimidazo [1, 2_a] pyridine was adsorbed and collected on the column. The column was washed with ImL of water, and then ImL of ethanol was passed through to elute [ ¹²⁵ 1] _2_ (4, monohydroxyphenyl) _6-deidoimidazo [1, 2_a] pyridine. The amount of radioactivity obtained was 3 immediately after synthesis. 7. It was 5MBq. In addition, as measured by TLC analysis under the same conditions as in Reference Example 6, the radiochemical purity was 96.5%.

[0110] (Reference Example 8) [ ¹²³ 1] Synthesis of IMPY

 [0111] The following steps are used for the comparative example in the study on LogP and brain accumulation.

 octanol

According to the above, [ ¹²³ I] _IMPY was synthesized.

[0112] According to the method described in the literature (Zhi-Ping Zhuang et al., J. Med. Chem, 2003, 46, p.237-243), 6 _tributylstannyl_ 2_ [4, _ (^ ^, N-dimethylamino) phenyl] imidazo [1,2_a] pyridine was synthesized and dissolved in methanol (concentration: lmgZmL). 53 μU of this solution, lmol / L hydrochloric acid 100 L, 190-240 MBq of [ ¹²³ 1 Kouwi 匕 sodium 20-50 μL, ImmolZL sodium iodide solution 10 x L, 10% (WZV) hydrogen peroxide 10 μL I made a mistake. The mixture was allowed to stand at 50 ° C. for 10 minutes, and then subjected to HPLC under the same conditions as in Reference Example 4 to fractionate [ ¹² ¾-IMPY fraction.

[0113] A solution obtained by adding 10 mL of water to the fraction was passed through a reverse-phase column (trade name: Sep-Pak (registered trademark) Light C18 Cartridges, Waters, packing amount of filler: 130 mg), [ ¹² ¾—I MPY was adsorbed and collected on the column. The column was washed with 1 mL of water, and 1 mL of ethanol was then passed through to elute [ ¹²³ 1] -IMPY. The amount of radioactivity obtained was 47-56 MBq immediately after synthesis. When TLC analysis was performed under the same conditions as in Reference Example 4, the radiochemical purity was 98.0%.

 [0114] (Example 1) Synthesis of 6-methoxy-2- [4 '-(3 "-paratoluenesulfonyloxypropoxy) phenyl] imidazo [1,2-a] pyridine

[0115] After dissolving 100 · 0 g of 2-bromo-3-hydroxypyridine (equivalent to 0.575 mol) in 310 mL of dimethyl sulfoxide, 575 mL of lmol / L sodium methoxide / methanol solution (equivalent to 0.575 mol) was prepared. The reaction solution was heated to 90 ° C. and methanol was distilled off. After cooling the reaction solution to 10 ° C or lower, 93.9 g (corresponding to 0.662 mol) of yowi methinole was added and stirred at room temperature for 20.5 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted twice with black mouth form. The combined black mouth form layer was washed with ImolZL sodium hydroxide and then washed twice with saturated saline. After drying this over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 65.4 g (0.348 mol) of 2_bromo_3 methoxypyridine (FIG. 1, step 1). [0116] 262 mL of concentrated sulfuric acid was cooled to 2 ° C, and 262 mL of 90% nitric acid was carefully added thereto, and then 65.3 g (corresponding to 0.347 mmol) of 2-bromo-3-methoxypyridine was carefully added. The resulting mixture was stirred in an ice bath for 10 minutes, then stirred at room temperature for 30 minutes, further heated to 55 ° C. and stirred for 1.5 hours. After cooling the reaction solution, it was gradually poured into ice to form a precipitate, which was collected by filtration and washed with water. The resulting precipitate was dried under reduced pressure in the presence of diphosphorus pentoxide to obtain 55.7 g (corresponding to 0.239 mmol) of 2_bromo_3-methoxy_6_nitropyridine (Figure 1, step 2). ).

 [0117] 2_Bromo_3-methoxy-6_nitropyridine 55.6 g (equivalent to 0.239 mol) was dissolved in 1700 mL of ethanol, and under an argon stream10. /. After adding 37.3 g of palladium on carbon (50% wet), 283 mL of hydrazine monohydrate was added dropwise. The reaction mixture was heated to reflux for 70 minutes, and then the reaction solution was cooled to room temperature and palladium carbon was filtered. The filtrate was washed with ethanol, and the washing solution was combined with the filtrate. After concentrating this solution under reduced pressure, 1300 mL of water and 130 mL of concentrated aqueous ammonia were added and extracted eight times with black mouth form. The combined chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was distilled under reduced pressure to obtain 26.2 g of 2-amino-5-methoxypyridine (corresponding to 0.211 mol). (Figure 1, step 3).

 [0118] 50 mL of ethyl acetate is suspended in 28.17 g (corresponding to 126 mmol) of cupric bromide, and then 8 · 18 g (corresponding to 60. Ommol) of 4'-hydroxyacetophenone is added in 50 mL of ethyl acetate. A solution dissolved in 50 mL of mouth form was collected and heated to reflux. After 5 hours, the reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and after decolorization operation with activated carbon, the solution was filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (eluent: chloroform / methanol = 20/1) and recrystallized from ethyl acetate / petroleum ether, 2_bromo_4 7.25 g (corresponding to 33.7 mmol) of '-hydroxyacetophenone was obtained (Fig. 1, step 4).

[0119] 2.15 g (corresponding to 10. Ommol) of 2-bromo-1,4-hydroxyacetophenone and 1.25 g of 2-amino-1-methoxypyridine (10. Ommol of wood) were dissolved in 50 mL of acetonitrile. The mixture was heated to reflux for 3.5 hours in an oil bath at 90 ° C. After completion of the reaction, the reaction solution was cooled to room temperature, and the precipitate was filtered off. The precipitate separated by filtration was washed with acetonitrile and dried under reduced pressure to obtain crude crystals. The obtained crude crystals are suspended in a mixture of 40 mL of water and 40 mL of methanol. About 20 mL of sodium bicarbonate solution was added, and the mixture was shaken with an ultrasonic cleaner for 5 minutes. The precipitate was filtered off, washed well with water, dried under reduced pressure, and 1.96 g (equivalent to 8.16 mmol) of 2- (4'-hydroxyphenyl) -6-methoxyimidazo [1,2-a] pyridine was obtained. Obtained (Figure 1, step 5).

[0120] 1, 3 _Propanediol 1. 45 mL (equivalent to 20. Ommol) is dissolved in 200 mL of methylene chloride, and 6.96 g (30. 666 mg (equivalent to 4.0 mmol) and paratoluenesulfuryl chloride 4.21 g (equivalent to 22. Ommol) were added, and the mixture was stirred at room temperature for 3 hours. Insoluble matter was filtered from the reaction mixture, and the insoluble matter was further washed with ethyl acetate. The filtrate and washings were combined and concentrated, and the resulting crude product was purified by flash silica gel chromatography (eluent: hexane / ethyl acetate = 3Z2 → lZl) to obtain 1,3_propanediol monoparaffin. 2.47 g (corresponding to 10.7 mmol) of toluenesulfonate was obtained (Fig. 1, step 6).

 [0121] 1,3_Propanediol monoparatoluenesulfonate 554mg (equivalent to 2.40mmol) in tetrahydrofuran 10mL solution, 2- (4, monohydroxyphenyl) 6-methoxyimidazo [1,2-a] pyridine 260mg ( l. 08 mmol application) and 636 mg of triphenylenophosphine (equivalent to 2.42 mmol) were added, and 5 mL of N, N dimethylformamide was added to completely dissolve the contents. To the reaction mixture, 0.48 mL (equivalent to 2.42 mmol) of diisopropylazodicarboxylate was added and stirred at room temperature for 23 hours, and then the reaction solution was concentrated. The resulting crude product was purified by flash silica gel column chromatography (eluent: black mouth form / ethyl acetate = 19/1), and further recycled preparative HPLC (HPLC apparatus: LC-908 (product name, Japan) Analytical Industrial Co., Ltd.), column: JAIGEL 2H (product name, manufactured by Nihon Analytical Industrial Co., Ltd.) is connected in two, mobile phase: Chloroform form, and purified again using flash silica gel column chromatography (eluent: to 2- [4 '-(3 "-paratoluenesulfonyloxypropoxy) phenyl] _6 methoxyimidazo [1,2-a] pyridine 220mg (equivalent to 0.487mmol) (Figure 1, Step 7).

[0122] The NMR measurement results (internal standard substance: tetramethylsilane) of the obtained compound were as follows.

 [0123] NMR apparatus used: JNM- ECP-500 (manufactured by JEOL Ltd.)

iH NMR (solvent: heavy chloroform, resonance frequency: 500 MHz): δ 7.81-7.77 (m, 2H), 7.76-7.72 (m, 2H), 7.71-7.70 (m, IH), 7.64-7.62 (m, IH), 7.49-7.46 (m, 2H), 7.24-7.21 (m, 2H), 6.95—6.92 (m , IH), 6.81-6.77 (m, 2H), 4.25 (t, J = 6.0 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 2.34 (s, 3H) , 2.11 (quint., J = 6.0

Hz, 2H).

[0124] ¹³ C_NMR (solvent: heavy chloroform, resonance frequency: 125 MHz): δ 158.16, 149.11, 145 • 41, 144.77, 142.71, 132.64, 129.75, 127.71, 126.93, 126.85, 119.45, 117.28, 114.4 7, 108.35 , 107.49, 66.99, 62.97, 56.11, 28.77, 21.52.

[0125] (Example 2) 2 _ [4 '- (3 "_ [18 F] Full O b propoxy) Hue sulfonyl] - 6-Metokishiimida zone [1, 2 _ a] pyridine

[ ¹⁸ F] fluoride ion-containing H ¹⁸ 〇 (radioactivity 5087 MBq, correction value at the start of synthesis), Se

 2

The solution was passed through p-Pak Light QMA (trade name, manufactured by Nippon Waters Co., Ltd.), and [ ¹⁸ F] fluoride ions were adsorbed and collected. Next, an aqueous solution of potassium carbonate (66.7 mmol / L, 0.3 mL) and 20 mg (equivalent to 53.1 / i mol) of acetonitrile with 1.5 mL of a solution of potassium carbonate (66.7 mmol / L, 0.3 mL) were passed through the column. And [ ¹⁸ F] fluoride ions were eluted.

 [0127] This was heated to 100 ° C under a flow of helium gas to evaporate water, and then acetonitrinol (0.3 mL X 2) was added and azeotroped to dryness. Here, 2- [4,1 (3 "-paratoluenesulfonyloxypropoxy) phenyl] -6-methoxyimidazo [1,2-a] pyridine synthesized in Example 1 above 5 mg of N, N-dimethylformamide 1 · OmL solution was added and heated for 10 minutes at 130 ° C.After cooling the reaction solution to 30 ° C, the reaction solution was charged with 3. ethyl acetate, Sep- Pak Plus Silica (trade name, Japan) The mixture was further passed through Sep- Pak Plus Silica twice with a mixture of 3.5 mL of jetyl ether and 0.5 mL of Ν, N-dimethylolenolemamide 0.5 mL. The solution was heated to 60 ° C. under aeration of helium gas and concentrated, and diluted by adding 2 mL of a mixture of acetonitrile, water Z, triethylamine = 550: 450: 1.

[0128] The obtained solution was HPLC (column: SUMIPAX ODS JP—06 (20 mmi. D. X 250 mm, manufactured by Sumika Chemical Analysis Center), eluent: acetonitrile, water Z, triethylamine = 500/50 0/1, flow rate : 7.5 mL / min). After diluting the eluent fraction containing the target product with 50 mL of water, add this solution to Sep_Pak Plus C18 (trade name, date). The target product was adsorbed and collected. Next, 20 mL of water was passed through the column for washing, and then 2 mL of ethanol was passed through and eluted to give 2- [4 '-(3 "— [ ¹⁸ F] fluoropropoxy) phenyl] 6-methoxyimidazo [1 , 2 a] Pyridine in ethanol was obtained, and the amount of radioactivity obtained was 1795 MBq (94 minutes after the start of synthesis), and TLC analysis was performed under the following conditions. %Met.

[0129] TLC analysis conditions:

 TLC plate: Silica Gel 60 F (product name, manufactured by Merck)

 254

 Developing phase: black mouth form / methanol / triethylamine = 50/1/2

 Detector: Rita Star (product name, manufactured by raytest)

[0130] (Examples 3-5, Comparative Examples 1-5) Amyloid affinity measurement

 The amyloid affinity of the compound of the present invention was evaluated by the following in vitro binding test.

[0131] (1) Αβ (Peptide Institute) (hereinafter referred to as Α / 3) with phosphate buffer (pH 7.4)

 1-40 1-40

 After dissolution, the mixture was shaken at 37 ° C. for 62 to 72 hours to obtain a lmg / mL aggregated AiS suspension (hereinafter referred to as amyloid suspension in this example).

 [0132] (2) For the above amyloid suspension, use Thioflavin T (Fluka) according to the method described in the literature (Naiki, Tsuji et al., Laboratory Investigation.! ^ Ρ 3 74-383 (1996)). Qualitative experiments were performed by measuring the fluorescence intensity, and it was confirmed that the aggregated A obtained in (1) was amyloid (measurement conditions: excitation wavelength 446 nm, fluorescence wavelength 490 nm).

 [3] (3) 2- (4 ′ aminophenyl) benzothiazole was used as a labeling precursor according to the method described in the literature (Wang, Tsuji et al., J. Labeled Compounds Radiopharmaceut.M, S239 (2001)).

[ ¹²⁵ 1] 2- (3, 1,4,1-aminophenyl) benzothiazole (hereinafter, [ ¹² ¾3'-I-BTA-0) was prepared and dissolved in ethanol. Congo Red, Thioflavin T and 6_Methyl_2_ [4 '_ (N, N-dimethylamino) phenyl] benzothiazole (hereinafter 6_Me_BTA_2) were used after weighing commercially available reagents.

[0134] (4) 2— (3, __ do_4, monoaminophenyl) benzothiazole (hereinafter 3, _I_BTA_0) and IMPY are described in the literature (Wang, Y. et al., J. Labeled Compounds Radiopharmaceut. 44 S239). (2001)) and the literature (Zhuang, ZP et al., J. Med. Chem., 237 (2003)). [0135] (5) ⁵ 3 ′ I BTA—0, 0.1% bovine serum albumin-containing phosphate buffer (pH 7.4) so that the final concentrations of each evaluation compound and amyloid are as shown in Table 2. Samples dissolved in 1 were prepared and filled into each well (volume: about 0.3 mL) of a 96-well microplate.

 [0136] [Table 2] Table 2 Final concentration of each compound in the sample solution

[0137] (6) The microplate filled with the sample solution, 3 hours at 22 ° C, After shaking at a constant speed (400 rpm Z min), each sample solution glass fiber filter (trade name: Multiscreen ^{T M} - [ ¹² ¾ 3, 1 I 1 B TA-0 and [ ¹²⁵ I] 3, _I_BTA_0 not bound to amyloid were separated by filtration through FC, manufactured by Millipore).

 [7138] (7) The glass fiber filter used for the filtration of each sample solution was washed with 0.1% bovine serum albumin-containing phosphate buffer (pH 7.4) (0.5 mL x 5 times). The radioactivity of the glass fiber finolators was measured with the Otouer 'gamma system (Aloka, model: ARC-301B), and used for the calculation of the inhibition rate as the radioactivity of each sample solution. The radioactivity in a sample of 0 is A, and the radioactivity in a sample with an evaluation compound concentration of 0.OOlnmol / L or more is B).

[8139] (8) Separately, 6-Me—BTA-2 was mixed with 15 i mol / L, [ ¹² ¾ 3, 1 I—BTA-0 was mixed with 400 pmol / L, and A iS was mixed with 1 μmol / L. And the same operation as in (6) and (7) above.

 1 -40

 The amount of radioactivity was measured. The obtained radioactivity was used as the background radioactivity and used to calculate the inhibition rate (hereinafter referred to as BG).

(9) Using the radioactivity measured in the above (7) and (8), the following formula (1):

[0141] [Equation 1] ^{fi ~ gG xl00 (%) (} 1)

 A-BG

[0142] The inhibition rate was determined. A graph was prepared by plotting the value obtained by probit conversion of the obtained inhibition rate against the logarithm of the concentration of the evaluation compound, and an approximate straight line was prepared by the method of least squares. Using this straight line, the concentration of each evaluation compound was determined so that the amount of radioactivity was half of the value in the sample to which no evaluation compound was added, and the 50% inhibitory concentration (hereinafter referred to as IC value) of each compound was determined. This

 50%

 As an index, the affinity of each evaluation compound for amyloid (aggregated Aβ) was evaluated.

 1-40

 It was.

 [0143] Table 3 shows the IC value of each evaluation compound. Compounds 1-3 are all less than 100 IC

 50%

 Amyloid (aggregated A) higher than Congo Red and Thioflavin 示 し

50% had 1-40 affinity. From this result, compounds 1 to 3 show good amyloid (aggregated A

 1-

) It was shown to be a compound with affinity. In particular, in Compound 1, 3'-I

40

-BTA-0 and 6-Me-BTA-2 were also high and had affinity for amyloid (aggregated A _J 3) equivalent to IMPY.

 -40

[0144] [Table 3] Table 3 IC _{5 Q ¾} values of the compounds of the present invention

(Example 6, Comparative Example 6) Measurement of partition coefficient using octanol extraction method

[0146] The partition coefficient (hereinafter referred to as logP) using the octanol extraction method, which is generally known as an indicator of the permeability of the compound to the blood brain barrier (hereinafter referred to as BBB), was measured.

 octano 丄

[0147] 10 mL of a solution containing Compound 4 (Example 5) in 2 mL of octanol and 10 mmol / L phosphoric acid 2 mL of buffer solution (pH 7.4) was added and stirred for 30 seconds. This mixture is centrifuged (2000 rpm / min x 60 min) with a low-speed centrifuge (Hitachi Co., Ltd., model: CENTRIFUGE CT4D). The performance was measured with an Autowell gamma system (Aloka, model: ARC-301B). The logP value was calculated from Equation (2) using the obtained radioactivity.

 [0148] [Equation 2] Radiation capacity of Octanol layer

, ₀ 水層の放射能カウント ( 2 )

, ₀ Radioactivity counts in water layer (2)

[0149] The results are shown in Table 4. For compounds that are permeable to BBB, the logP value is between:! And 3

 octanol

 (Douglas D. Dischino et al., J. Nucl. Med., (1983), 24, p. 1030-1038). Compound 4 has a logP value of 1.8, similar to IMPY in the comparative example.

 octanol

 It was suggested to have BBB permeability.

[0150] [Table 4] Table 4 1 ο g P of the compound of the present invention. _etan . > Value

[0151] (Examples 7 to 9, Comparative Example 7) Measurement of partition coefficient using HPLC

 [0152] The partition coefficient by HPLC (hereinafter referred to as logP) was measured by the following method. This log

 HPLC

 P is logP, which is generally known as an index of BBB permeability of compounds, and pH 7

HPLC octanol

It is a numerical value known to have an equivalent value in 2 to 7 · 4 (Franco Lombar do et al., J. Med. Chem., (2000), 43, ρ · 2922- 2927).

[0153] First, each evaluation compound shown in Table 5 was dissolved in methanol containing 10% dimethyl sulfoxide so as to have a concentration of 1 mg / mL to prepare a sample solution. The sample solution 1 was subjected to HPLC analysis under the following conditions. The solvent elution time (t) and the compound elution time (t

 0 R

) [0154] [Table 5]

 Table 5 Evaluation compounds in each experiment

[0155] HPLC conditions:

 Column: Prodigy ODS (3) (product name, manufactured by phenomenex, size: 4.6 x 250 mm) Mobile phase: 50 mM triethylamine phosphate (pH 7.2) / acetonitrile = 40/60 mixture Flow rate: 0 7mL / min

 Detector: UV-Vis spectrophotometer (Detection wavelength: 282nm)

[0156] Using the obtained t and t, the retention factor (hereinafter referred to as “retention factor”) of each evaluation compound is calculated from the formula (3).

 0 R

 (Hereinafter, κ, value).

 HPLC

[0157] [Equation 3] HPLC ⁼ (tR― to) 'to ■ "V 3)

[0158] Separately, the [ ¹² ¾ _ 2_ (4,-(3, _fluoropropoxy)] ferro 6 rhododazo [1, 2-a] pyridine solution (radioactivity) synthesized in Reference Example 6 above Concentration 37MBqZmL) and [ ¹² ¾—2— (4, -hydroxyphenyl) -6-odoimidazo [1,2_a] pyridine solution (radioactivity concentration 37MBq / mL) synthesized in Reference Example 7 above 10 μL each was added to 2 mL of the prepared octanol, and 2 mL of lOmmolZL phosphate buffer solution (ρ H7.4) was added to each solution. Centrifugation was carried out for 60 minutes under the same conditions, measuring 1 mL each of the octanol phase and the aqueous phase, and measuring the radioactivity with an Otowell gamma system (Aloka, model: ARC-301B). From the above, the logP value was calculated using the above equation (2).

 octanol

[0159] Furthermore, 2- (4,1 (3 "fluoropropoxy) phenyl 6-imidazole [1, 2-a] pyridine solution synthesized in Reference Example 4 and the above Reference Example 5 were synthesized. The same HPLC analysis was performed on each of the 2- (4′-hydroxyphenyl) -6 pseudoimidazo [1,2-a] pyridine solution to obtain the K ′ value. -Fluoropropoxy) 6-Choidoimidazo [1,2-a] pyridine-Hydroxyphenyl) 6-Chocoidimidazo [1,2-a] pyridine

[ ¹² ¾— 2— (4, 1 (3, 1 Fluoropropoxy)) 6

10 HPLC

 Create a graph plotting the logP values for imidazo [1,2_a] pyridine and [I] 1-2_ (4,1hydroxyphenyl) _6_ odoimidazo [1,2_a] pyridine.

 octanol

 The y intercept was estimated. Using this value, the logP value and logP value are between pH 7.2 and 7.

 octanol HPLC

 Assuming 4 and 4 are equal, the following equation (4) is obtained.

(log, οΛ '„,,,.,■) +1,59 … (4) [Equation 4]

(log, οΛ '„,,,., ■) +1,59… (4)

[0162] Using K ′ obtained for each evaluation compound, each evaluation was performed according to the above equation (4).

 HPLC

 The logP value for the compound was determined.

 HPLC

 [0163] The results are shown in Table 6. As shown in this table, the logP value is

 HPLC

 Even though: showed values between:! As mentioned above, the logP value is known to be between 1 and 3 for compounds that are permeable to BBB (Douglas D. Dischi

 octanol

 no et al., J. Nucl. Med., (1983), 24, p. 1030-1038). LogP and logP are pH

 octanol HPLC

7. It is known to have a same value in 2~7.4 (. Franco Lombardo et al, J.Med.Chem, (2000), 43, p.2922-2927) from ₀ above results, the compound: It was suggested that! ~ 3 has the property of permeating the BBB.

[0164] [Table 6]

(Example 10, Comparative Example 8) Measurement of brain migration and clearance

[0166] Time course of radioactivity accumulation in the brain of male Wistar rats (7 weeks old) using Compound 4 Changes were measured.

[0167] A solution prepared by dissolving Compound 4 in a physiological saline containing 10 mg / mL ascorbic acid and the above-described Reference Example 8 [ ¹² ¾- IMPY (Comparative Example 7) was prepared as a physiological salt containing 10 mg / mL ascorbic acid. Each 0.05 mL of the solution dissolved in the solution (radioactive concentration 15 to 31 MBq / mL) was administered to the rats through the tail vein under thiopental anesthesia. At 2, 5, 30, and 60 minutes after administration, blood was collected from the abdominal aorta and the brain was collected, and the radioactivity in the brain was measured using the Autoll 'gamma system (form: ARC_ 301B, manufactured by Aloka). (Hereinafter referred to as A in this example), and the brain mass was further measured. In addition, the amount of radioactivity was measured in the same manner for 0.05 mL of a 1000-fold diluted solution (hereinafter referred to as “B” in this example). Using these measurement results, the radioactivity distribution rate (% 107 §) per unit weight to the brain at each dissection time point was calculated from the following formula (5). The experiment was performed using three animals at each time point.

 [0168] [Equation 5]

% ID / g = ^ X 100… (5)

 B X 1000 X Brain mass

The results are shown in Table 7. As shown in Table 7, Compound 4 showed an accumulation equal to or greater than ¹²³ I_IMP at 2 minutes after administration, and then showed a tendency to disappear rapidly over 60 minutes. From these results, it was suggested that Compound 4 has high brain migration and rapid clearance from the brain, similar to ¹²³ I-IMPY.

 [0170] [Table 7] Table 7 Radioactivity accumulation in the brain after intravenous administration of the compound of the present invention (rat)

[Example 11] Confirmation of visualization of amyloid in the brain

[0172] In order to evaluate whether the compound according to the present invention can depict amyloid in the brain, the following experiment was conducted. [0173] (1) Dissolve Αβ (Wako Pure Chemical Industries) in phosphate buffer (ρΗ7.4) and shake at 37 ° C for 72 hours

1 -42

 Then, a lmg / mL aggregated Aj3 suspension (hereinafter referred to as amyloid suspension in this example) was obtained.

[0174] (2) 2.5 _U L (equivalent to 2) of the above amyloid suspension was injected into one side of the amygdala of male Wistar rats (7 weeks old) and, as a control, phosphate buffer was added to the amygdala on the other side 2. Saline solution (pH 7.4) was injected. Rats 3 days after the injection of amyloid suspension and phosphate buffered saline (pH 7.4) were used as specimens.

 [0175] (3) Compound 4 was dissolved in 1 OmgZmL ascorbic acid-containing physiological saline to give a sample solution (radioactivity concentration 84 MBqZmL). This solution was administered to the rat through the tail vein (dose: 0.5 mL, dosed radioactivity: equivalent to 42 MBq).

 [0176] (4) The brain was removed 30 minutes after administration, and a brain section having a thickness of 10 x m was prepared using a microtome (format: CM3050S, manufactured by LEICA). The brain section was exposed on an imaging plate for 1.5 hours, and then image analysis was performed using a bioimaging analyzer (form: BAS-2500, manufactured by Fuji Photo Film Co., Ltd.).

 [0177] (5) After completion of the above image analysis using a bioimaging analyzer, pathological staining with thioflavin Τ was performed and fluorescence microscope (Nikon Corporation, model: TE2000—U type, excitation wavelength: 400-440 nm, detection Imaging using a wavelength of 470 nm) confirmed that amyloid was deposited on the section (FIG. 9b).

 [0178] Fig. 9 shows images of autoradiogram and thioflavin T staining in brain sections of rats injected with amyloid in the brain. As shown in this figure, the amygdaloid nucleus on the side injected with the amyloid suspension had a clear radioactivity accumulation and a good image with little non-specific accumulation at other sites. . In addition, the results of thioflavin T staining at the radioactive accumulation site confirmed that amyloid was present at the site where accumulation was observed. On the other hand, no significant radioactivity accumulation was confirmed in the amygdaloid nucleus on the side injected with phosphate buffered saline as compared with other sites.

 From these results, it was suggested that Compound 4 has the ability to accumulate in brain amyloid and has the ability to visualize brain amyloid.

[0179] (Examples 12-: 14) Reverse mutation test [0180] In order to examine the gene mutagenicity of Compound 1, Compound 2 and Compound 3, a reverse mutation test (hereinafter referred to as Ames test) using TA98 and TA100 of Salmonella typhimurium was carried out. went.

 [0181] The test was conducted with no S9mix and with S9mix. Negative subjects use dimethyl sulfoxide, and positive subjects use 2_ (2_furyl)-3-(5 —nitro _ 2_furyl) acrylamide when S9mix is not added, and 2_aminoanthra when S9mix is added. Sen was used.

 [0182] Each sample was added to the test plate at a maximum dose of 1250 xg / plate for Compound 1, 7 doses (common ratio 4), and 5000 z gZ plates for Compound 2 and Compound 3. The highest dose was 7 doses (public ratio 3). The test substance and the test strain (TA98 or TA100), or the test substance, S9mix and the test strain were mixed, and then layered on the medium on the test plate using soft agar and cultured at 37 ° C for 48 hours. Judgment was made by counting the number of revertant colonies in the plate after culturing, and when the number of revertant colonies showed a value more than twice that of the negative control and further increased depending on the concentration. Positive.

 [0183] The results are shown in Table 8. The number of reverse mutation colonies in the treatment groups of Compound 1, Compound 2 and Compound 3 was less than twice that of the negative control regardless of the presence or absence of S9mix supplements. On the other hand, the positive control substance-treated group showed a clear increase in the number of revertant colonies. Based on the above results, Compound 1, Compound 2 and Compound 3 were determined to be Ames negative and determined not to have gene mutagenicity.

 [0184] [Table 8] Table 8 Results of A m e s test

 Mutagenicity

 Compound S9mi No additive S9mi Caro

 TA98 TA100 TA98 TA100

Example 1 2 Compound 1 Negative Negative Negative Negative Example 1 3 Compound 2 Negative Negative Negative Negative Example 1 4 Compound 3 Negative Negative Negative Negative Industrial applicability

 [0185] The compounds according to the present invention can be used in the field of diagnostic agents.

 Brief Description of Drawings

 [0186] [Fig. 1] Synthesis scheme of 6-methoxy-2- [4 '-(3 "-paratoluenesulfonyloxypropoxy) phenino] imidazo [1,2-a] pyridine.

 [Fig. 2] Synthesis scheme of 2- [4 '-(3 "fluoropropoxy) phenyl] 6-methoxyimidazo [1,2-a] pyridine (non-radioactive fluorinated product).

 [Fig. 3] Synthesis scheme of 2— [4,1 (3 ”fluoropropoxy) phenyl] -6-hydroxyimidazo [1,2-a] pyridine (non-radioactive fluorinated compound).

 [Fig.4] Synthesis scheme of 2_ [4,-(3 "_fluoropropoxy) phenyl] imidazo [1, 2_a] pyridine (non-radioactive fluorinated product).

 [Fig. 5] Synthesis scheme of 2 _ (4, _ (3 "_ fluorpropoxy) phenyl _ 6- odorimidazo [1, 2 _ a] pyridine.

 [Fig.6] Synthetic scheme of 2- (4,1hydroxyphenyl) 6-6-imidazo [1,2-a] pyridine.

[Fig. 7] [ ¹² ¾_2_ (4 '_ (3 ,, _ Fluoropropoxy) phenyl 1-6 odoimidazo [1, 2-a] pyridine synthesis scheme.

[FIG. 8] Synthesis scheme of [ ¹² ¾_2_ (4'-hydroxyphenyl) _6_ odoimidazo [1, 2_a] pyridine.

 [FIG. 9] (a) Autoradiogram in brain section 30 minutes after administration of Compound 4 and (b) Fluorescent micrograph of thioflavine T-stained sample (enlarged display of amyloid suspension administration site.)

Claims

Claim [1] Formula (1) below: [Chemical 1]

(In the formula, R ¹ is a group selected from hydrogen, a hydroxyl group, a carboxyl group, a sulfate group, an amino group, a nitro group, a cyano group, an alkyl substituent having 1 to 4 carbon atoms, or an alkoxy substituent having 1 to 4 carbon atoms. R ² is a radioactive halogen substituent,  m is an integer of 0-2. Or a salt thereof. [2] The compound or salt thereof according to claim 1, wherein R ² is selected from the group consisting of ¹⁸ F, ⁷⁶ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I or ¹³¹ I force. [3] The compound or a salt thereof according to claim 1 or 2, wherein R ² is ¹⁸ F. [4] Formula (2) below: [Chemical 2]

(Wherein R ³ is a group selected from hydrogen, a hydroxyl group, a carboxyl group, a sulfate group, an amino group, a nitro group, a cyano group, an alkyl substituent having 1 to 4 carbon atoms, or an alkoxy substituent having 1 to 4 carbon atoms. R ⁴ is a group selected from a non-radioactive halogen substituent, a methanesulfonic acid substituent, a trifluoromethanesulfonic acid substituent or an aromatic sulfonic acid substituent,  m is an integer of 0-2. Or a salt thereof.  [5] Formula (1) below: [Chemical 3]

(In the formula, R ¹ is a group selected from hydrogen, a hydroxyl group, a carboxyl group, a sulfate group, an amino group, a nitro group, a cyano group, an alkyl substituent having 1 to 4 carbon atoms, or an alkoxy substituent having 1 to 4 carbon atoms. R ² is a radioactive halogen substituent,  m is an integer of 0-2. ) A low-toxicity diagnostic agent for Alzheimer's disease comprising a compound represented by the above formula or a salt thereof. 6. The low toxicity Alzheimer's disease diagnostic agent according to claim 5, wherein R ² is selected from the group consisting of ¹⁸ F, ⁷⁶ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I or ¹³¹ I. [7] R ² is a ¹⁸ F, low toxicity Alzheimer's disease diagnostic agent according to claim 5 or 6, wherein. [8] An amyloid deposit comprising the compound represented by the formula (1) according to any one of claims 1 to 3 or a salt thereof and a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition for in vivo imaging.  [9] A compound represented by the formula (1) or a salt thereof according to any one of claims 1 to 3, which is used for pharmaceutical use.  [10] The compound represented by formula (1) or a salt thereof according to any one of claims 1 to 3, which is used for in vivo imaging of amyloid deposits. [11] (a) any one of claims 1 to 3, the step of administering a detectable amount of the compound represented by the formula (1) or the salt thereof according to 1;  (b) detecting binding of said compound or salt thereof to amyloid deposits in a patient, and detecting the patient's amyloid deposits in vivo. 12. The method according to claim 11, wherein the step (b) is performed by PET or SPECT imaging.